Glaucoma affects over 70 million people worldwide and is associated with an optic nerve fiber atrophy that results in progressive visual loss. (Quigley (1996) BR. J. OPHTHALMOL. 80:389-393; Resnikoff et al. (2004) Bull. WORLD. HEALTH ORGAN. 82:844-851; Weinreb et al. (2004) LANCET 363:1711-1720). Although increased intraocular pressure (IOP) is widely recognized as a major risk factor, the pathogenesis of the disease remains unclear. Lowering IOP is currently the only standard treatment to prevent disease progression, though some patients with significant IOP reduction or even normal IOP still show disease progression. (Heijl et al. (2002) ARCH. OPHTHALMOL. 120:1268-1279; Iwase et al. (2004) OPHTHALMOLOGY 111:1641-1648.) Among the cells in the eye, RGCs are particularly vulnerable in glaucoma. (Levin (2003) Surv. Ophthalmol. 48:S21-24.) Neuroprotection of RGCs has been emphasized as an important goal for managing the disease, although this has yet to achieved. Id.
Tumor necrosis factor-α (TNFα) is synthesized primarily by activated monocytes as a 26 kDa precursor which is proteolytically cleaved and secreted as a 17 kDa protein. (Brouckaert et al. (1993) IMMUNOBIOLOGY 187:317-329; Moss et al. (1997) J. NEUROIMMUNOL. 72:127 129.) TNFα acts through either the low-affinity (TNFR1) or high-affinity TNF receptor (TNFR2). (Tartaglia et al. (1992) IMMUNOL. TODAY 13:151-153.) TNFα is upregulated in several neurodegenerative disorders, including multiple sclerosis, Parkinson's Disease, and Alzheimer's Disease, and in optic nerve microglia and astrocytes of glaucoma patients. (Shohami et al. (1999) CYTOKINE GROWTH FACTOR REV. 10:119-130; Yan el al. (2000) ARCH. OPHTHALMOL. 118:666-673; Yuan et al. (2001) J. NEUROSCI. RES. 64:523-532; Yuan et al. (2000) GLIA 32:42-50.) TNFα gene polymorphisms increase the risk for glaucoma, suggesting that TNFα may contribute to the pathogenesis of the disease. (Funayama et al. (2004) INVEST. OPHTHALMOL. VIS. SCI. 45:4359-4367.) TNFα is toxic to immunopurified RGCs and to RGCs in mixed cultures when glia are stressed, though not under resting conditions. (Tezel et al. (2004) CURR. OPIN. OPHTHALMOL. 15:80-84; Fuchs et al. (2005) INVEST. OPHTHALMOL. VIS. SCI. 46:2983-2991.) In vivo, exogenous TNFα prevents RGC death after optic nerve damage, though other studies show that it can cause the loss of RGC axons and a delayed loss of somata. (Diem et al. (2001) J. NEUROSCI. 21:2058-2066; Kitaoka et al. (2006) INVEST. OPHTHALMOL. VIS. SCI. 47:1448-1457.) There has been no direct evidence that TNFα contributes to RGC death in glaucoma, nor any mechanistic understanding of how this might occur.
The loss of RGCs is delayed by several weeks after elevating IOP in experimental glaucoma models. (Cordeiro et al. (2004) PROC. NATL. ACAD. SCI. USA 101:13352-13356; Huang et al. (2005) PROC. NATL. ACAD. SCI. USA 102:12242-12247; Ji et al. (2005) VISION RES. 45:169 179.) Because of the difficulty in manipulating important molecules over this duration, genetically altered mice can be used for investigating the significance of candidate molecules in disease progression. Although the establishment of the DBA/2J mouse line with a spontaneous mutation that leads to glaucoma has contributed to research in this field, the utility of these animals for investigating pathophysiological mechanisms is limited by a relatively long delay in RGC loss and by considerable inter-individual variability. (John (2005) INVEST. OPHTHALMOL. VIS. SCI. 46:2649-2661.) Laser-induced glaucoma models allow for a convenient, rapid induction of ocular hypertension (OH), and can be done in genetically altered mice to study molecular mechanisms underlying RGC loss. (Lindsey et al. (2005) J. GLAUCOMA 14:318-320.)
Glaucoma is a progressive optic neuropathy, which can induce blindness without any warning and often without symptoms. Glaucoma is characterized by a buildup of fluid within the eye, often causing an increase in IOP. The pressure increase damages the optic nerve, resulting in cellular death and vision loss. In a healthy eye, the fluid that contains nutrients and that bathes the eye is continuously drained and replenished. However, in a person with glaucoma, this fluid either does not drain properly or too much is created, resulting in an increase in intraocular pressure. The elevated IOP, if left untreated, eventually damages the optic nerve.
As a result, lowering IOP using medical or surgical therapy is the main therapeutic approach to control and treat this common condition. The currently available treatments, however, have their own problems. Most medications have side effects, lose their efficacy, and require patients' lifetime compliance. Surgical methods have a high complication risk. Ciliary body destruction by cryotherapy or laser irradiation represents a useful alternative for the management of glaucoma resistant to other modes of therapy. (Bietti (1950) JAMA, 142:889-897, Wekers et al. (1961) AM. J. OPHTHALMOL. 52:156-63, Smith el al. (1969) AM. J. OPHTHALMOL. 67:100-10.) However, the current cyclodestructive techniques have a high rate of side-effects including loss of vision, hypotony, macular edema or phthisis bulbi. (Beckman et al. (1984) AM. J. OPHTHALMOL. 98:788-95; Haddad (1981) WIEN. KLIN. WOCHENSCHR. SUPPL. 126:1-18; Kaiden et al. (1979) ANN. OPHTHALMOL. 11:1111-3.)
Accordingly, there is still an ongoing need for new methods for treating glaucoma, but without the side effects of other currently available treatments.